Synthesis of N,N,N’,N’ -tetraalkylbenzidines through oxidative coupling of N,N -dialkylarylamines induced by SbCl 5

The oxidative coupling to 4,4’-N , N , N ’, N ’-tetraalkylbenzidines is the main reaction observed during a study on the reactivity of N , N -dialkylanilines with SbCl 5 . A possible reaction mechanism is presented and discussed in comparison with the N , N -dialkylanilines oxidative coupling achieved with other Lewis acids


Introduction
Antimony pentachloride reacts with monoalkylbenzenes or deactivated aromatic compounds, providing an aromatic chlorination by electrophilic aromatic substitution either as a direct chlorinating agent, 1-5 or as a catalyst of the chlorination with chlorine gas, 6 because of the combination of its Friedel-Crafts catalytic activity and its oxidation-reduction potential.Some hypotheses have been proposed to explain the higher aromatic para/ortho-chlorination ratio observed with SbCl5, in comparison to the reactions with Cl2/SbCl5, a bulky electrophilic species (SbCl4 + /SbCl6 + ) being postulated in the former case. 1,7-8 At variance with the above mentioned substrates, no studies on the reactivity of SbCl5 with anilines or other arylamines were carried out.During the study of some N,N-disubstituted anilines, 9 we undertaken an investigation on the reactivity of a wide number of substituted benzenes in the presence of Lewis acids, and we found that after treatment of N,N-dialkylanilines with SbCl5, followed by neutralization with a base, N,N,N',N'-tetralkylbenzidines can be isolated in fair to good yields from the reaction mixture.
Interestingly, in the used experimental conditions, SbCl5 does not seem to react with anilines as a direct chlorinating agent, and N,N,N',N'-tetralkylbenzidines were the main reaction products.
Since substituted benzidines are interesting and useful compounds, for their application in the field of organic solar cells, photoconductors, oLED and other devices, we found interesting to investigate in detail such a new synthetic methodology to N,N,N',N'-tetraalkylbenzidines.

Results and Discussion
We found that the treatment of N,N-disubstituted anilines 1a-d with SbCl5, followed by neutralization with a base (aqueous KOH or K2CO3 ), afforded N,N,N',N'-tetralkylbenzidines 2ad in fair to good yields, together with little amounts of chlorinated products (Scheme 1 and Table 1).The formation of insoluble red-brown powders (named from now on, solids 3a-c) was observed in the course of all reactions after SbCl5 addition to the N,N-disubstituted aniline solution in CH2Cl2.However, some efforts aimed at the isolation of such intermediates in solid crystalline form, from the reaction mixture before the final basic treatment, failed. 10Scheme 1. Products of reaction of N,N-dialkylanilines 1a-d with SbCl5.
a Reaction conditions: SbCl5/C6H5NR2 (1:1 ratio) were stirred for 24 h under nitrogen atmosphere before treatment with K2CO3 (See Experimental).In this conditions SbCl5 does not react with anilines as a direct chlorinating agent, and N,N,N',N'-tetralkylbenzidines were the main reaction products.
Oxidative coupling of N,N-dialkylarylamines to benzidines is a known reaction, 7,8,11 and the formation of 4,4'-N,N,N',N'-tetraalkylbenzidines by reaction of N,N-dialkylanilines with some transition metals (CAN, 12 TiCl4, 13 etc.) has also been reported.In particular, to explain the oxidative coupling observed in the reaction of N,N-dialkylarylamines with TiCl4, 13 a stepwise mechanism has been proposed, that involves the formation of two complexes with TiCl4 (adduct 1N-Ti and 1C-Ti), followed by the conversion of 1C-Ti into a radical cation intermediate (Scheme 2 ).Scheme 2. Mechanistic hypothesis of 4,4'-N,N,N',N'-tetraalkylbenzidines formation by oxidative coupling of N,N-dialkylanilines in the presence of TiCl4.However, a similar mechanism could not to be proposed when SbCl5 was used, since a very unusual oxidation number +4 should be required for the Sb species (SbCl4) detachment in this case (Scheme 3).Scheme 3. Mechanistic hypothesis of 4'-N,N,N',N'-tetraalkylbenzidines formation by radical oxidative coupling of N,N-dialkylanilines in the presence of SbCl5.So, we propose an alternative mechanistic hypothesis (Scheme 4), where the dimerization is just the result of a direct interaction between the starting N,N-dialkylaniline and the 1N-Sb adduct.Based on this hypothesis, the formation of the 1C-Sb intermediate depicted in Scheme 3 should be excluded.Scheme 4. Mechanistic hypothesis of oxidative coupling of N,N-dialkylanilines in the presence of SbCl5.
Since some spectroscopic and analytical data collected for the solid intermediates 3a-c precipitated from the reaction mixture were consistent with the N 4 ,N 4 ,N 4' ,N 4' -tetraalkylbiphenyl-4,4'-diaminium structures (Scheme 4), we carried out some experiments to investigate the nature of that reaction intermediates and to deepen the synthetic applications of such reaction.
First, different experimental conditions have been explored, and the collected data showed that better yields of benzidines 2a-d can be obtained in the presence of stoichiometric amounts of SbCl5 (Table 2).
Subsequently, we performed some specific coupling experiments to clarify the nature of our reaction intermediates, aimed at definitively exclude the hypothesis of their "aniline" structure (e.g., adduct 1C-Sb, Scheme 3) and/or confirming its "benzidinium" nature, as depicted in Scheme 4.
We isolated the two solid-intermediates 3a and 3c from the reaction of SbCl5 with N,Ndimethylaniline 1a and N,N-diisopropylaniline 1c, respectively.Then, equimolecular amounts of 3a and 3c were mixed and heated under reflux in the presence of KOH (Scheme 5).The reaction mixtures were stirred for 24 h under nitrogen atmosphere after quenching with aq.K2CO3 (See Experimental).b 3% of chlorinated products were also observed.
As a result, only the symmetric benzidines 2a and 2c were obtained (Scheme 5), and no cross-coupling reactions were observed, as expected if the solids 3a and 3c had the adducts 1C-Sb structures.

Scheme 5
Next, we studied the reaction between N,N-diisopropylamine 1c and the solid 3a: this experiment provided the symmetrical substituted benzidine 2a, together with some starting unreacted aniline 1c (Scheme 6).

Scheme 6
Conversely, little amounts of 2f was detected in the reaction of an equimolecular mixture of the two anilines 1a and 1c with SbCl5, followed by the basic treatment (aq.KOH) (Scheme 7).The different conversion of the two anilines could be due to the different rate of reaction of the starting materials.

Scheme 7
All the results collected in the above described coupling experiments are consistent with the hypothesis that in the reaction with SbCl5, the C-C formation between the two N,Ndialkylarylamines moieties plausibly takes place before the final basic treatment: consequently, the structure of adduct 1C-Sb (and the following radical intermediate of Scheme 3) are not consistent with the nature of the solid intermediates 3a-d.
Based on the above results, we proposed that the benzidines formation could occur plausibly through a SE mechanism, as hypothesized in Scheme 4, where the dimerization could be explained as the result of a preliminary interaction of SbCl5 with the arylamine nitrogen of one molecule, followed by the coupling of the 1N-Sb adduct with a second molecule of the starting aniline.
According to that hypothesis, the dimerization step should be rate determining, and a decrease of reactivity should be observed with sterically hindered substrates.
As expected, low reactivity was observed in the reaction of 1-N,N-dimethylnaphthylamine (1g) with SbCl5 (Scheme 8), probably due to the involvement of two species (naphthylamine and ammonium adduct), both with a hindered α-position.

Scheme 8
However, since has been reported that SbCl5 reacts through the formation of cation-radical intermediates in similar reaction conditions, 14 a radical mechanism hypothesis could not definitively be excluded.Further investigations are actually in progress on this point, aimed also to a full characterization of the reaction intermediates 3a-c by X-ray crystallography.

Conclusions
In conclusion, in this investigation SbCl5 was found to promote oxidative coupling of N,Ndialkylarylamines to benzidines.On the basis of specific coupling experiments, and spectroscopic and analytical data collected for the solid intermediates 3a-c, the benzidines formation could be explained as the result of a preliminary interaction of SbCl5 with the nitrogen atom of one arylamine molecule, followed by the coupling of this N-adduct with a second molecule of the starting aniline.However, since SbCl5 reacts through the formation of cationradical intermediates, 14 a radical mechanism hypothesis could not definitively be excluded.Further investigations are in progress on this point, aimed to a full characterization of the reaction intermediates 3a-c by X-ray crystallography.Other investigations are also in progress to optimize the yields of the formation of not-symmetrically substituted benzidines and/or other different coupling products.
The oxidative coupling of aniline derivatives here reported provides a new synthetic methodology to N,N,N',N'-tetraalkylbenzidines, that are actually interesting studied and used for their electric conductivity in the field of organic solar cells, photoconductors, oLED and other interesting devices. 15-18

Experimental Section
General.Melting points taken on Electrothermal apparatus were uncorrected. 1H NMR spectra were recorded on a VARIAN XL-200, a Varian-Mercury 300 MHz, a Varian-Inova-400 MHz, a Bruker-Aspect 3000 console-500 MHz spectrometers and chemical shifts are reported in parts per million ().Absolute values of the coupling constant are reported.FT-IR spectra were recorded on a Perkin-Elmer 681 spectrometer.GC analyses were performed on a HP 6890 model, Series II by using a HP1 column (methyl siloxane; 30 m x 0.32 mm x 0.25 μm film thickness).Analytical thin-layer chromatography (TLC) was carried out on pre-coated 0.25 mm thick plates of Kieselgel 60 F254 visualisation was accomplished by UV light (254 nm) or by I2 vapour.Column chromatography was conducted by using silica gel 60 with a particle size 40-63 μm and 230-400 ASTM.Petroleum ether refers to the 40-60 °C boiling fraction.GC-MS analyses were performed on HP 5995C model and elemental analyses on an Elemental Analyzer 1106 Carlo Erba instrument.CH2Cl2 was distilled from CaH2 under nitrogen; N,N-dialkylarylamines and all the other chemicals and solvents were commercial grade and used without further purification.Due to its toxicity, SbCl5 (purchased from Aldrich Chemical Co.) must be handled with extreme caution and with dry utensils.All the operations must be done with care away from water and only in a functioning chemical fume hoods.N,N,N',N'-tetraalkylbenzidines 2 and the halogenated products of the reactions had analytical and spectroscopic data identical to those of commercially available compounds or previously reported in literature.The percentage of Cl for Elemental Analysis of solids 3a-c was determined by Schöniger method. 19

General Procedure for the isolation of Sb-intermediates 3a-c by reaction of N,Ndialkylarylamines with SbCl5 (Schemes 5-8).
To a solution of N,N-dialkylarylamine (1a-c) (0.960 mL, 5 mmol) in freshly distilled CH2Cl2 (5 mL) kept at 0 °C, a solution of SbCl5 (0.633 mL, 5 mmol) in CH2Cl2 (5 mL) was dropwise added, in a nitrogen-flushed three necked flask equipped with a magnetic stirrer, nitrogen inlet and two dropping funnels.The reaction mixture was stirred for 24 h at room temperature, and then the red-coloured solid intermediate precipitated during the reaction was filtered under vacuum and under nitrogen atmosphere, washed with anhydrous CH2Cl2, and the solvent residue evaporated under reduced pressure.